DESCRIPTION: (Adapted from the applicant's abstract.) The long-term goal of this research program is to delineate the pathophysiological effects of, and the adaptive mechanisms to chronic hypoxia (CH). CH is seen in man living at high altitude (HA) and also occurs in patients suffering from heart or lung dysfunction. CH invariably elicits polycythemia, pulmonary hypertension (PH) and hypoxemia but peculiarly, these pathophysiological processes become more severe in some individuals or species leading to fatal cardiopulmonary complication. The pathogenesis of the intra- and inter-specific susceptibility to these untoward consequences of CH remains a challenging issue to physiologists and clinicians. The animal models for this study consist of two strains of rats with differing susceptibility to CH. Following CH, Hilltop (H) rats develop excessive polycythemia and severe PH associated with high mortality (signs of chronic mountain sickness [CMS]). Madison (M) rat develop only moderate polycythemic and cardiopulmonary responses with apparent good health. Excessive polycythemia is the most important etiological factor leading to the development of CMS. A recent study by the applicant shows that an exaggerated production of erythropoietin (EPO) and an accentuated hypoxemia that develops following CH are the primary causes of the excessive polycythemia observed in H rats. There are two specific aims in this project: The first aim is to evaluate the roles of the following two possible mechanisms in the exaggerated EPO production in H rats during two weeks' hypoxic exposure: 1) severe renal cortical tissue hypoxia. Tissue hypoxia in H and M rats will be probed by analyzing hypoxic metabolites (Lactate, NADH etc.) as well as EPO in different regions of renal cortex, and 2) inordinate sensitivity of EPO production to hypoxic stimulation and the underlying mechanisms. Prostaglandin (PGE2, PGI2), cAMP, EPO mRNA and EPO in various regions of renal cortex in H and M rats will be analyzed to assess this problem. The second aim is to test the hypothesis that severe PH and/or hypoxic pulmonary vasoconstriction (HPV) and/or polycythemia developed in H rats following CH could be involved in accentuating the hypoxemia. The specific roles of these various factors will be assessed by determining whether experimentally induced reduction in PH, and/or HPV and/or polycythemia could reverse the accentuated hypoxemia in H rats and whether an increase in these factors could lead to accentuation of the hypoxemia in M rats, using chronically instrumented and fully awake animals.